Atherosclerotic coronary artery disease (CAD) remains a major cause of death and disability. New biological discoveries are required to transform our understanding of the disease and to spur clinical and therapeutic advances. Of CAD loci identified through recent genome wide association studies (GWAS), many have no apparent association with established risk factors or known mechanisms of atherosclerosis. Few new loci, however, have the combination of a clear candidate gene at the locus, plausible biology, and preliminary evidence that suggest specific translational hypotheses. Through GWAS, we discovered and replicated ADAMTS7 as a novel locus for coronary atherosclerosis. This finding has been reproduced in two other large-scale GWAS initiatives. ADAMTS7 has no relationship to traditional risk factors. This metalloproteinase, however, is expressed in human vascular smooth muscle cell (VSMC) and atherosclerotic lesions and our preliminary studies suggest that Adamts7-/- gene deletion in mice reduces the in vivo neointimal response to femoral artery injury. We hypothesize that ADAMTS7 promotes transition to VSMC synthetic phenotype and accelerates atherosclerosis by cleaving cartilage oligomeric matrix protein (COMP) an endogenous brake on VSMC migration, proliferation and matrix secretion. Here, we propose a series of experiments to: (Aim 1) define ADAMTS7 structure-function for COMP and develop a high-throughput ADAMTS7 activity assay for use in mouse and human, (Aim 2) examine effects of germline loss-of-function (LOF) and gain-of-function (GOF) of Adamts7 on VSMC phenotype, vascular injury and atherosclerosis in mouse models, and (Aim 3) interrogate functional impact and CAD association of rare and low frequency non-synonymous ADAMTS7 alleles in human. Our investigative team is well positioned to execute these translational studies and advance our understanding of causation, directionality and mechanisms of ADAMTS7 action in atherosclerosis. PUBLIC HEALTH RELEVANCE: Through GWAS, we have identified and validated ADAMTS7 as a novel gene for coronary atherosclerosis and heart disease. Little is known of ADAMTS7 function in the vasculature. In this proposal, we will define structure-function of ADAMTS7 interactions with target proteins, assess the effects of loss of function and gain of function on mouse atherosclerosis and VSMC function, and interrogate non-synonymous variants discovered upon sequencing of ADAMTS7 in humans for potential loss of function mutations that reduce risk of CAD. Our team is well positioned to advance understanding of ADAMTS7 mechanisms in atherosclerosis, thus establishing if this enzyme might be a valid therapeutic target for heart disease.